Ceftriaxone is a third-generation cephalosporin antibiotic and its sodium salt is commonly used in clinical practice. Ceftriaxone sodium has great antibacterial activity against a variety of gram-negative bacteria and some gram-positive bacteria (such as Escherichia coli, Klebsiella pneumoniae, Neisseria gonorrhoeae and the like), and can be used for the treatment of infectious diseases caused by sensitive bacteria. However, there is a certain limit on the application of ceftriaxone sodium due to its insensitivity to Methicillin-Resistant Staphylococcus aureus (MRSA) and Enterobacter cloacae. Sulbactam is a β-lactamase inhibitor. In the prior art, sulbactam sodium and ceftriaxone sodium are formulated into a compound formulation, which improves the antimicrobial spectrum and sensitivity of ceftriaxone to drug-resistant bacteria.
Stable quality of a drug is critical for ensuring the safety of drug use. The crystalline form (crystalline morphology) of a crude drug plays a very important role in stabilizing the drug quality. Regarding the quality control of a drug, different crystalline forms (crystalline morphologies) of the drug may have different stability and thus affect the drug quality. If the crystalline form (crystalline morphology) of a drug is determined, the quality of the drug would be more stable and be easier to be controlled; otherwise, the drug quality would vary from batch to batch, resulting in different stability of different batches.
Prior research showed that ceftriaxone sodium can have many different crystalline morphologies. A single crystal structure of ceftriaxone sodium was simulated by means of a software, and provides useful reference for researchers on the crystal of ceftriaxone sodium. Ceftriaxone sodium has three sub-crystalline forms which have differences in all the following aspects: salt-forming rate, crystallinity, compatibility with butyl rubber closures and the like. These sub-crystalline forms of ceftriaxone sodium probably affect the efficacy of drugs.
Sulbactam sodium is also a substance which may be present in different crystalline forms. Sulbactam sodium may be crystallized from a mixed solvent of ethyl acetate and n-butanol, and its single crystal structure is also disclosed. Sulbactam sodium was prepared by using different solvents such as acetone, ethyl acetate, methanol, ethanol and the like, resulting in four different kinds of crystal which varied significantly in morphology, density and flowability. A sulbactam crystal can be formed, and the content of sulbactam can be maintained within 24 months.
In order to obtain pharmaceutical compound formulations of ceftriaxone sodium and sulbactam sodium with better efficacy as compared with single prescription preparations, it is necessarily required that the pharmaceutical compound formulations have stable quality. However, the compound formulations show greater complexity in the respect of preparation, efficacy and the like, as compared with the single prescription preparations. In the respect of crystalline form, both ceftriaxone sodium and sulbactam sodium have multiple different crystals as shown in the prior art, which results in the complexity of the crystalline form of the compound drug. Further, the preparation of the compound drug may also have an unpredictable effect on the crystal production of ceftriaxone sodium and sulbactam sodium.
Studies have found that the known compound preparations of ceftriaxone sodium and sulbactam sodium have unstable crystalline forms.
Under a condition of low temperature and inert gas, ceftriaxone sodium, sulbactam sodium and a lyoprotectant were dissolved in 70% ethanol to form a solution; the solution was added with a pH adjusting agent and subjected to lyophilization to form a eutectic powder, in which the active ingredient substantially did not degrade within 36 months. However, the eutectic powder comprised many components such as ceftriaxone sodium, sulbactam sodium, a lyoprotectant, a pH adjusting agent and the like, which might have certain effect on the crude drug itself. Studies have shown that the eutectic powder had a stable content, but had no stable crystal formed therein, which means that it was still unstable in the sense of crystallography.
Crystal is a substance in which the particles are arranged in an ordered microscopic structure. While the presence mode of the crystal cannot be predicted effectively, due to the limitations of scientific and technological level nowadays. Inventors expect to improve the quality of product, lengthen the shelf life, and improve the economy and safety of the compound formulation of ceftriaxone sodium and sulbactam sodium through in-depth research.